Novel microRNAs targeting NMDA receptor subunits in animal models of schizophrenia

2021 ◽  
Author(s):  
Sowmya Gunasekaran ◽  
Reena S. Jacob ◽  
Ramakrishnapillai V. Omkumar
Keyword(s):  
Cognitive Deficits ◽  
Hippocampal Neurons ◽  
Transcript Levels ◽  
Neuregulin 1 ◽  
Mk 801 ◽  
Methylazoxymethanol Acetate ◽  
Protein Levels ◽  
Bioinformatic Tools ◽  
Primary Hippocampal Neurons ◽  
Translational Arrest

AbstractN-methyl-D-aspartate receptors (NMDAR) are downregulated in schizophrenia possibly through microRNAs (miRNAs) that are differentially expressed in this condition. We screened the miRNAs that are altered in schizophrenia against the targets, Grin2A and Grin2B subunits of NMDAR using bioinformatic tools. Among the predicted miRNAs some interacted with the 3’-UTR sequences of Grin2A (miR-296, miR-148b, miR-129-2, miR-137) and Grin2B (miR-296, miR-148b, miR-129-2, miR-223) in dual luciferase assays. This was supported by downregulation of the GluN2B protein in primary hippocampal neurons upon overexpressing Grin2B targeting miRNAs. In two models of schizophrenia-pharmacological MK-801 model and neurodevelopmental methylazoxymethanol acetate (MAM) model which showed cognitive deficits - protein levels of GluN2A and GluN2B were downregulated but their transcript levels were upregulated. MiR-296-3p, miR-148b-5p and miR-137 levels showed upregulation in both models which could have interacted with Grin2A/Grin2B transcripts resulting in translational arrest. In MAM model, reciprocal changes in the expression of the 3p and 5p forms of miR-148b and miR-137 were observed. Expression of neuregulin 1 (NRG1), BDNF and CaMKIIα, genes implicated in schizophrenia, were also altered in these models. This is the first report of downregulation of GluN2A and GluN2B by miR-296, miR-148b and miR-129-2. Mining miRNAs regulating NMDA receptors might give insights into the pathophysiology of this disorder, providing avenues in therapeutics.

scholarly journals Absence of Thyroid Hormone Induced Delayed Dendritic Arborization in Mouse Primary Hippocampal Neurons Through Insufficient Expression of Brain-Derived Neurotrophic Factor

2021 ◽  
Vol 12 ◽  
Author(s):  
Hiroyuki Yajima ◽  
Izuki Amano ◽  
Sumiyasu Ishii ◽  
Tetsushi Sadakata ◽  
Wataru Miyazaki ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Neurotrophic Factor ◽  
Hippocampal Neurons ◽  
Brain Derived Neurotrophic Factor ◽  
Mrna Levels ◽  
Protein Levels ◽  
Primary Hippocampal Neurons ◽  
Developmental Impairment

Thyroid hormone (TH) plays important roles in the developing brain. TH deficiency in early life leads to severe developmental impairment in the hippocampus. However, the mechanisms of TH action in the developing hippocampus are still largely unknown. In this study, we generated 3,5,3’-tri-iodo-l-thyronine (T3)-free neuronal supplement, based on the composition of neuronal supplement 21 (NS21), to examine the effect of TH in the developing hippocampus using primary cultured neurons. Effects of TH on neurons were compared between cultures in this T3-free culture medium (-T3 group) and a medium in which T3 was added (+T3 group). Morphometric analysis and RT-qPCR were performed on 7, 10, and 14 days in vitro (DIV). On 10 DIV, a decreased dendrite arborization in -T3 group was observed. Such difference was not observed on 7 and 14 DIV. Brain-derived neurotrophic factor (Bdnf) mRNA levels also decreased significantly in -T3 group on 10 DIV. We then confirmed protein levels of phosphorylated neurotrophic tyrosine kinase type 2 (NTRK2, TRKB), which is a receptor for BDNF, on 10 DIV by immunocytochemistry and Western blot analysis. Phosphorylated NTRK2 levels significantly decreased in -T3 group compared to +T3 group on 10 DIV. Considering the role of BDNF on neurodevelopment, we examined its involvement by adding BDNF on 8 and 9 DIV. Addition of 10 ng/ml BDNF recovered the suppressed dendrite arborization induced by T3 deficiency on 10 DIV. We show that the lack of TH induces a developmental delay in primary hippocampal neurons, likely caused through a decreased Bdnf expression. Thus, BDNF may play a role in TH-regulated dendritogenesis.

scholarly journals Neuregulin 1/ErbB4 signaling attenuates neuronal cell damage under oxygen-glucose deprivation in primary hippocampal neurons

2019 ◽  
Vol 52 (4) ◽  
pp. 462 ◽  
Author(s):  
Ji-Young Yoo ◽  
Han-Byeol Kim ◽  
Seung-Yeon Yoo ◽  
Hong-Il Yoo ◽  
Dae-Yong Song ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Cell Damage ◽  
Neuronal Cell ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Neuregulin 1 ◽  
Primary Hippocampal Neurons

Effects of mood-stabilizing drugs on dendritic outgrowth and synaptic protein levels in primary hippocampal neurons

2014 ◽  
Vol 17 (3) ◽  
pp. 278-290 ◽  
Author(s):  
Sung Woo Park ◽  
Jung Goo Lee ◽  
Mi Kyoung Seo ◽  
Hye Yeon Cho ◽  
Chan Hong Lee ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Synaptic Protein ◽  
Protein Levels ◽  
Primary Hippocampal Neurons

scholarly journals Vitamin E Improves Neurite Complexity by Enhancing Mitochondrial Function

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 915-915
Author(s):  
Han-A Park ◽  
Kristi Crowe-White ◽  
Abigail Davis ◽  
Sydni Bannerman ◽  
Garret Burnett ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vitamin E ◽  
Neurite Outgrowth ◽  
Mitochondrial Function ◽  
Hippocampal Neurons ◽  
Brain Diseases ◽  
Control Group ◽  
University Of Alabama ◽  
Protein Levels ◽  
Primary Hippocampal Neurons

Abstract Objectives Neurite outgrowth is a foundational process in brain development and recovery from brain injury. Assembly of the cytoskeleton and formation of new synapses during neurite outgrowth requires an abundance of energy. We have reported that the mitochondrial protein Bcl-xL is necessary for neurite outgrowth and arborization. However, Bcl-xL undergoes post-translational cleavage during oxidative stress resulting in a product that impairs mitochondrial function. Our recent publication demonstrated that treatment with alpha-tocotrienol, an antioxidant member of the vitamin E family, prevents cleavage of Bcl-xL and protects neurons from oxidative stress. In this study, we hypothesize that treatment with alpha-tocotrienol improves mitochondrial function to support the energy demanding processes of growth and development in the neurons. Methods Primary hippocampal neurons were grown in neurobasal media with or without alpha-tocotrienol for 3 weeks. Then, the number of neurite branches was quantified applying Sholl analysis. We also assayed the ATP/ADP ratio at neurites using the PercevalHR fluorescence biosensor. mRNA and protein levels of total Bcl-xL and cleaved Bcl-xL were measured using real time PCR and immunoblotting. Results Neurons grown with alpha-tocotrienol achieved more advanced neurite complexity than the control group. Treatment with alpha-tocotrienol enhanced both total ATP and local neurite ATP levels in primary hippocampal neurons. Furthermore, we found that alpha-tocotrienol Increased mRNA and protein levels of Bcl-xL without enhancing post-translational cleavage of Bcl-xL, consistent with our previous study. Conclusions Our data show that alpha-tocotrienol improves mitochondria-mediated ATP production by enhancing Bcl-xL to support metabolically demanding processes in neurons. We suggest a novel function of alpha-tocotrienol in normal physiological development of the brain. This study also suggests a potential therapeutic role of alpha-tocotrienol in brain diseases associated with neurite injury. Funding Sources RGC Program (University of Alabama) Crenshaw Research Fund (University of Alabama).

ATRA-induced increase in intracellular Ca2+concentration in primary hippocampal neurons

2010 ◽  
Vol 34 (8) ◽  
pp. S74-S74
Author(s):  
Tingyu Li ◽  
Xiaojuan Zhang ◽  
Xuan Zhang ◽  
Jian Hea ◽  
Yang Bi Youxue Liu ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Primary Hippocampal Neurons

MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Dan Wang ◽  
Zhifu Fei ◽  
Song Luo ◽  
Hai Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Western Blot ◽  
Mrna Expression ◽  
Cognitive Deficits ◽  
Protein Levels ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

Schisandrin Restores the Amyloid β-Induced Impairments on Mitochondrial Function, Energy Metabolism, Biogenesis, and Dynamics in Rat Primary Hippocampal Neurons

Pharmacology ◽  
2021 ◽  
pp. 1-11
Author(s):  
Zhongyuan Piao ◽  
Lin Song ◽  
Lifen Yao ◽  
Limei Zhang ◽  
Yichan Lu
Keyword(s):  
Energy Metabolism ◽  
Cytochrome C ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Hippocampal Neurons ◽  
Citrate Synthase ◽  
Mitochondrial Permeability Transition ◽  
Amyloid Β ◽  
Mitochondrial Functions ◽  
Primary Hippocampal Neurons

Introduction: Schisandrin which is derived from Schisandra chinensis has shown multiple pharmacological effects on various diseases including Alzheimer’s disease (AD). It is demonstrated that mitochondrial dysfunction plays an essential role in the pathogenesis of neurodegenerative disorders. Objective: Our study aims to investigate the effects of schisandrin on mitochondrial functions and metabolisms in primary hippocampal neurons. Methods: In our study, rat primary hippocampal neurons were isolated and treated with indicated dose of amyloid β1–42 (Aβ1–42) oligomer to establish a cell model of AD in vitro. Schisandrin (2 μg/mL) was further subjected to test its effects on mitochondrial function, energy metabolism, mitochondrial biogenesis, and dynamics in the Aβ1–42 oligomer-treated neurons. Results and Conclusions: Our findings indicated that schisandrin significantly alleviated the Aβ1–42 oligomer-induced loss of mitochondrial membrane potential and impaired cytochrome c oxidase activity. Additionally, the opening of mitochondrial permeability transition pore and release of cytochrome c were highly restricted with schisandrin treatment. Alterations in cell viability, ATP production, citrate synthase activity, and the expressions of glycolysis-related enzymes demonstrated the relief of defective energy metabolism in Aβ-treated neurons after the treatment of schisandrin. For mitochondrial biogenesis, elevated expression of peroxisome proliferator-activated receptor γ coactivator along with promoted mitochondrial mass was found in schisandrin-treated cells. The imbalance in the cycle of fusion and fission was also remarkably restored by schisandrin. In summary, this study provides novel mechanisms for the protective effect of schisandrin on mitochondria-related functions.

Neurotrophic Properties of Silexan, an Essential Oil from the Flowers of Lavender-Preclinical Evidence for Antidepressant-Like Properties

2020 ◽  
Vol 54 (01) ◽  
pp. 37-46
Author(s):  
Kristina Friedland ◽  
Giacomo Silani ◽  
Anita Schuwald ◽  
Carola Stockburger ◽  
Egon Koch ◽  
...  
Keyword(s):  
Essential Oil ◽  
Hippocampal Neurons ◽  
Day Treatment ◽  
Neuronal Cell ◽  
Antidepressant Activity ◽  
In Vivo Models ◽  
Antidepressant Effects ◽  
Primary Hippocampal Neurons

Abstract Background Silexan, a special essential oil from flowering tops of lavandula angustifolia, is used to treat subsyndromal anxiety disorders. In a recent clinical trial, Silexan also showed antidepressant effects in patients suffering from mixed anxiety-depression (ICD-10 F41.2). Since preclinical data explaining antidepressant properties of Silexan are missing, we decided to investigate if Silexan also shows antidepressant-like effects in vitro as well as in vivo models. Methods We used the forced swimming test (FST) in rats as a simple behavioral test indicative of antidepressant activity in vivo. As environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology—resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function—we investigated the neurotrophic properties of Silexan in neuronal cell lines and primary hippocampal neurons. Results The antidepressant activity of Silexan (30 mg/kg BW) in the FST was comparable to the tricyclic antidepressant imipramine (20 mg/kg BW) after 9-day treatment. Silexan triggered neurite outgrowth and synaptogenesis in 2 different neuronal cell models and led to a significant increase in synaptogenesis in primary hippocampal neurons. Silexan led to a significant phosphorylation of protein kinase A and subsequent CREB phosphorylation. Conclusion Taken together, Silexan demonstrates antidepressant-like effects in cellular as well as animal models for antidepressant activity. Therefore, our data provides preclinical evidence for the clinical antidepressant effects of Silexan in patients with mixed depression and anxiety.

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